CASE REPORT Open Access

Situs inversus totalis and secondary biliarycirrhosis: a case reportHacı Mehmet Sökmen1, Kamil Özdil1, Turan Çalhan1*, Abdurrahman Şahin1, Ebubekir Şenateş2, Resul Kahraman1,Adil Niğdelioğlu1 and Ebru Zemheri3

Abstract

Situs inversus totalis is is a congenital anomaly associated with various visceral abnormalities, but there is no dataabout the relationship between secondary biliary cirrhosis and that condition. We here present a case of a 58 year-old female with situs inversus totalis who was admitted to our clinic with extrahepatic cholestasis. After excludingall potential causes of biliary cirrhosis, secondary biliary cirrhosis was diagnosed based on the patient’s history,imaging techniques, clinical and laboratory findings, besides histolopathological findings. After treatment withtauroursodeoxycholic acid, all biochemical parameters, including total/direct bilirubin, alanine aminotransferase,aspartate aminotransferase, alkaline phosphatase and gama glutamyl transferase, returned to normal ranges at thesecond month of the treatment. We think that this is the first case in literature that may indicate the developmentof secondary biliary cirrhosis in a patient with situs inversus totalis. In conclusion, situs inversus should beconsidered as a rare cause of biliary cirrhosis in patients with situs inversus totalis which is presented withextrahepatic cholestasis.

Keywords: Situs inversus totalis, secondary biliary cirrhosis, tauroursodeoxycholic acid

BackgroundSitus inversus totalis (SIT) is a congenital anomaly char-acterized by complete transposition of abdominal andthoracic organs. As a birth defect in newborn infants, ithas an estimated incidence of 1/15000 to 10000 cases inlive births, with a male/female ratio of 3:2. Generally,this rare anomaly is diagnosed incidentally during thor-acic and abdominal imaging. The cause of situs inversus(SI) is unknown. More than one genetic mutationsincluding gene mutations which cause ciliopathy andcystic renal diseases were implicated in etiopathogenesis[1]. SIT is associated with various gastrointestinalabnormalities. In the current literature, development ofintestinal ischemia due to intestinal malrotation, andalso acute appendicitis and liver transplantation due tojuvenile biliary atresia were reported [2-4]. However,there is no data for the development of secondary biliarycirrhosis (SBC) due to extrahepatic cholestasis in apatient with SIT. We here presented a case of SIT with

SBC who referred to our clinic due to extrahepaticcholestasis.

Case presentationA 58-year-old female patient, who complained of icterusappearing in the last 6-7 months, along with the symp-toms of fatigue and loss of appetite continued for 2-3years, was referred to our clinic. According to her medi-cal history, she had been referred to a clinic because ofabdominal pain in the left lower quadrant and examineddue to acute abdominal pain when she was 6 years old.She had undergone a surgical operation due to acuteappendicitis located in the left lower quadrant and theSIT was diagnosed on those days. Furthermore, fre-quently recurrent upper respiratory tract infections,hypertension and a previous cholecystectomy (19 yearsago) were found in her medical history. The patient wasa smoker (26 packs/year) but she did not consume alco-hol. In detailed personal history, she did not have anyhepatotoxic drug usage in past three months. In her phy-sical examination, icteric appearance, moderate hepato-megaly and kyphosis was detected. Her initial laboratoryfindings were as follows: aspartate aminotransferase

* Correspondence: trncalhan@hotmail.com1Ümraniye Education and Research Hospital, Department ofGastroenterology, Istanbul, TurkeyFull list of author information is available at the end of the article

Sökmen et al. Comparative Hepatology 2011, 10:5http://www.comparative-hepatology.com/content/10/1/5

© 2011 Sökmen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

(AST) 232 U/L, alanine aminotransferase (ALT) 137 U/L,gama glutamyl transferase (GGT) 252 U/L, alkaline phos-phatase (ALP) 153 U/L, bilirubin (total/direct) 22.7/21.4mg/dl, albumin 2.5 g/dl, leucocyte 8100/mm3, hemoglo-bin 12.5 g/dl, platelet 216000/mm3, and INR 1.33. Urea,creatinine and electrolytes were in normal range. In addi-tion, markers of viral hepatitis (anti-HAV IgM, anti-HBcIgM, HBsAg, anti-HCV, TORCH), serology of autoim-mune hepatitis (anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-mitochondrialantibody (AMA), liver kidney microsomal antibody (anti-LKM), liver-cytosol spesific antibody (LC-1), anti-solubleliver antigene/liver pancreas (SLA/LP)), transferrinesaturation, ferritine and urine copper tests were also innormal ranges. An x-ray of the chest was reported toshow dextrocardia. On radiographic image of esophagusand gastric passage, gastric corpus was at the right side ofabdominal midline and pylorus and bulbus were locatedat the left side. In thoracic computed tomography (CT),dextrocardia and scars of previous pulmonary infectionswere observed (Figure 1). A paranasal sinus CT showedthe findings of chronic sinusitis (Figure 2). In transab-dominal ultrasonography (US), situs inversus totalis, mildheterogeneous liver parenchyma with grade I hepatostea-tosis, choledoc dilatation (11 mm) and mild splenome-galy were determined. Doppler ultrasonography of portalvein revealed a mild splenomegaly and dilated portal vein(14 mm). In endoscopic US, it was noted a choledochaldilatation without stone or sludge and with a diameter of11.9 mm. In endoscopic retrograde colangiopancreato-graphy (ERCP), performed after pharyngeal localanesthesia and sedation induced with pethidin (50 mg)and i.v. midazolam (5 mg), a dilatation in extrahepaticbiliary tracts was observed (Figure 3). Following endo-scopic sphincterotomy, extrahepatic biliary tracts wereswept by using basket and balloon catheter, but anystone or sludge was not extracted. Since an adequatedecrease in cholestasis parameters was not detected

after sphincterotomy, a liver biopsy was decided to beperformed. In the biopsy material, biliary stasis, rosetteformation, feathery degeneration, giant cell formationin lobules, diffuse fibrosis, ductal and ductular prolif-eration and lymphoplasmocytic infiltration in portalareas were observed (Figures 4, 5 and 6). SBC wasdiagnosed with patient’s history, imaging techniques,clinical and laboratory findings besides histologicalfindings. Thereupon, a 15 mg/kg/day dose of taurour-sodeoxycholic acid (TUDCA) was administrated to thepatient. During a follow-up period of 9 months, shehas been doing well. The laboratory parameters turnto normal ranges in two months and in follow-up per-iod, there was not any abnormal rising in laboratoryparameters.

Figure 1 Thoracic computed tomography scan. It showsdextrocardia and scars of previous pulmonary infections.

Figure 2 Paranasal sinus computed tomography scan. It showsclear chronic sinusitis.

Figure 3 Endoscopic retrograde colangiopancreatographyimages. The choledoc duct is dilated moderately and located onthe midline on vertebral axis.

Sökmen et al. Comparative Hepatology 2011, 10:5http://www.comparative-hepatology.com/content/10/1/5

Page 2 of 4

ConclusionsSI is associated with various gastrointestinal abnormal-ities such as absence of suprarenal inferior vena cava,polysplenia syndrome, preduodenal portal vein, duode-nal atresia or stenosis, tracheoeusophageal fistula (typeC), intestinal malrotation, aberrant hepatic arteria, hypo-plasia of portal vein, congenital hepatic fibrosis and bili-ary atresia [5]. In a previous study, it was found that thegallbladder may lie in the midline or be lateralized withthe bulk of the hepatic mass [6].

Although the etiology is not clear, it has been sug-gested that SIT and ciliopathy are related to each other.However, the mechanism has not been explainedentirely. It is suggested that the immobility of nodal ciliainhibits the flow of extra embryonic fluid duringembryonic period and this leads to SI development [7].However, primary ciliary dyskinesia (PCD) is observedonly in 25% of SI patients.Whereas a definition of congenital hepatic fibrosis asso-

ciated with ciliopathy and SIT is reported in the current lit-erature, there is no data about the concurrence of SIT andSBC. Our case is possibly the first one in literature in termsof such SIT and SBC co-existence. Despite there is no clearevident for the development of SBC in patients with SIT,considering the cases reported in literature, the followinghypotheses may be proposed. The cilium is a hair like struc-ture that extends from the cell surface into the extracellularspace and it has an axoneme containing microtubules, andthe microtubules connected with each other with dyneinarms that provide ciliary movement [8]. Electron micro-scopy of the ciliary microtubules frequently reveals absenceor abnormalities of the outer and/or inner dynein arms.Especially the mutations of the gene dynein axonemalheavy chain 11 (DNAH 11) are thought to be associatedwith ciliopathy and SI [9]. From various studies, it wasreported that ciliary dyskinesia has a role in the pathogen-esis of nephronophthisis (NPHP) and polycystic renal dis-ease (PCD) and the genes that are associated with renalcystic disease are important for left-right axis determinationof the body plan [10]. NPHP may be associated with liverfibrosis; patients develop hepatomegaly and moderate portalfibrosis with mild bile duct proliferation, this pattern differsfrom that of classical congenital hepatic fibrosis, wherebybiliary dysgenesis is prominent. Bile duct involvement in

Figure 4 Canalicular cholestasis, with rosette formation .Hematoxylin and eosin.

Figure 5 Portal fibrosis with ductular proliferation. Massontrichrome.

Figure 6 Ductal and ductular proliferation . Cytokeratin 7immunostaining.

Sökmen et al. Comparative Hepatology 2011, 10:5http://www.comparative-hepatology.com/content/10/1/5

Page 3 of 4

cystic kidney disease may be explained by the ciliary theory,because the epithelial cells lining bile ducts (cholangiocytes)possess primary cilia. It was suggested that especially themutations of the gene NPHP2/inversin is associated withSI. SI and ciliopathy also cause biliary dysgenenesis, dilata-tion of biliary tract and portal fibrosis [11,12].In our case, chronic rhinosinusitis and frequently

recurrent lower respiratory tract infections, abnormallocalization of the main biliary tract (on vertebral axis inERCP) and moderate dilated biliary tracts support thehypothesis of SIT and ciliopathy association.There is no data about increased incidence of chole-

lithiasis in SIT patients. Furthermore, in several casereports, it was suggested that pancreatic ductal carcinoma,autoimmune pancreatitis and sclerosing cholangitis maydevelop [13,14]. In our patient, there was not any pancrea-tic pathology. In magnetic resonance cholangiopancreato-graphy (MRCP), ERCP and endoscopic US examinations,there was no finding in favor of cholelithiasis, sclerosingcholangitis or malignity other than moderate choledochaldilatation. Hepatic transaminase enzymes and bilirubinvalues that were returned to normal ranges with the treat-ment of a 15 mg/kg/day dose of TUDCA within 2 monthssupported our diagnosis.Due to the following reasons, we consider SBC in this

case and not primary biliary cirrhosis (PBC): 1) first of all,antimitochondrial antibody was negative in this case; 2)secondly, there was not any symptomatic presentation thatseen in PBC such as pruritus, hyperpigmentation, xanta-lesma; 3) thirdly, in ERCP and MRCP images, choledocduct was moderately dilated and located on the midlineon vertebral axis; 4) finally, it is impossible to differentiatePBC or SBC in such a patient with stage 4 liver fibrosis,but the clinical features and laboratory findings along withhistopathological findings supported the SBC. The majorcauses of SBC are gallstones/choledocholityasis, narrowingof the bile duct following gallbladder surgery, chronic pan-creatitis, pericholangitis, idiaptahic sclerosing cholangitis,congenital biliary atresia and cystic fibrosis. In this case, allcauses of SBC mentioned above were excluded.We concluded that this is the first case in literature

that may indicate the development of SBC in a patientwith SIT.

ConsentWritten informed consent was obtained from the patientfor publication of this Case Report. A copy of the writ-ten consent is available for review by the Editor-in-Chiefof this journal.

Author details1Ümraniye Education and Research Hospital, Department ofGastroenterology, Istanbul, Turkey. 2Haydarpasa Numune Education andResearch Hospital, Department of Gastroenterology, Istanbul, Turkey.

3Göztepe Education and Research Hospital, Department of Pathology,Istanbul, Turkey.

Authors’ contributionsHMS carried out endoscopic ultrasonography (EUS) and participated incoordination and drafted the manuscript. KÖ carried out the endoscopicretrograde cholangiopancreaticography (ERCP), TÇ conceived of the casereport, and participated in its design and coordination and helped to draftthe manuscript. AŞ helped collecting the data of the patient. EŞ conceivedof the case report, and participated in its design and coordination andhelped to draft the manuscript. RK and AN followed the patients afterexternalization to date. EZ assessed the pathological materials of the patient.All authors read and approved the final manuscript.

Competing interestsThe authors declare that they have no competing interests.

Received: 7 May 2011 Accepted: 3 August 2011Published: 3 August 2011

References1. Hildebrandt F, Zhou W: Nephronophthisis-associated ciliopathies. J Am

Soc Nephrol 2007, 18(6):1855-1871.2. Wei JM, Liu YN, Qiao JC, Wu WR: Liver transplantation in a patient with

situs inversus: a case report. Chin Med J (Engl) 2007, 120(15):1376-1377.3. Asensio Llorente M, López Espinosa JA, Ortega López J, Sánchez

Sánchez LM, Castilla Valdez MP, Ferrer Blanco C, Margarit Creixell C, IglesiasBerengue J: [First orthotopic liver transplantation in patient with biliaryatresia and situsinversus in spain]. Cir Pediatr 2003, 16(1):44-47.

4. Cissé M, Touré AO, Konaté I, Dieng M, Ka O, Touré FB, Dia A, Touré CT:Appendicular peritonitis in situs inversus totalis: a case report. J MedCase Reports 2010, 4:134.

5. Lee SE, Kim HY, Jung SE, Lee SC, Park KW, Kim WK: Situs anomalies andgastrointestinal abnormalities. J Pediatr Surg 2006, 41(7):1237-1242.

6. Fonkalsrud EW, Tompkins R, Clatworthy HW Jr: Abdominal manifestationsof situsinversus in infants and children. Arch Surg 1966, 92(5):791-795.

7. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M,Hirokawa N: Randomization of left-right asymmetry due to loss of nodalcilia generating leftward flow of extraembryonic fluid in mice lackingKIF3B motor protein. Cell 1998, 95(6):829-837, Cell 1999, 99(1):117.

8. Cardenas-Rodriguez M, Badano JL: Ciliary biology: understanding thecellularand genetic basis of human ciliopathies. Am J Med Genet C SeminMed Genet 2009, 151C(4):263-280.

9. Bartoloni L, Blouin JL, Pan Y, Gehrig C, Maiti AK, Scamuffa N, Rossier C,Jorissen M, Armengot M, Meeks M, Mitchison HM, Chung EM, Delozier-Blanchet CD, Craigen WJ, Antonarakis SE: Mutations in the DNAH11(axonemal heavy chain dynein type 11) gene cause one form of situsinversus totalis and most likely primaryciliary dyskinesia. Proc Natl AcadSci USA 2002, 99(16):10282-10286.

10. Igarashi P, Somlo S: Genetics and pathogenesis of polycystic kidneydisease. J Am Soc Nephrol 2002, 13(9):2384-98.

11. Delaney V, Mullaney J, Bourke E: Juvenile nephronophthisis, congenitalhepatic fibrosis and retinal hypoplasia in twins. Q J Med 1978,47(187):281-90.

12. Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM, Ruf RG,Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T,Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G,Drummond IA, Benzing T, Hildebrandt F: Mutations in INVS encodinginversin cause nephronophthisis type 2, linking renal cystic disease tothe function of primary cilia and left-right axis determination. Nat Genet2003, 34(4):413-420.

13. Antonacci N, Casadei R, Ricci C, Pezzilli R, Calculli L, Santini D, Alagna V,Minni F: Sclerosing cholangitis, autoimmune chronic pancreatitis, andsitus viscerum inversus totalis. Pancreas 2009, 38(3):345-346.

14. Quintini C, Buniva P, Farinetti A, Monni S, Tazzioli G, Saviano L, Campana S,Malagnino F, Saviano M: [Adenocarcinoma of pancreas with situsviscerum inversus totalis]. Minerva Chir 2003, 58(2):243-246.

doi:10.1186/1476-5926-10-5Cite this article as: Sökmen et al.: Situs inversus totalis and secondarybiliary cirrhosis: a case report. Comparative Hepatology 2011 10:5.

Sökmen et al. Comparative Hepatology 2011, 10:5http://www.comparative-hepatology.com/content/10/1/5

Page 4 of 4